Historically, there have been major problems with the paradigm for the treatment of metastatic cancer. These include poor discrimation of drugs between host and cancer tissues, limited knowledge of appropriate targets, and inability to select patients who are likely to respond. Current advances, especially the introduction of targeted agents into the clinical setting, allow these critical issues to be addressed. We propose that the Phase I trial, which is the cornerstone for drug development, should be designed to provide basic knowledge regarding target impact and selection, upon which further trials can be built. In this regard, it is critical to recognize that molecularly targeted compounds may behave in a way that is fundamentally dissimilar to cytotoxic chemotherapy. For instance, targeted agents may be cytostatic, rather than cytotoxic, and only patients who bear a specific protein capable of being modulated by the drug may respond. Thus, rather than utilizing the standard paradigm for Phase I development of chemotherapeutic agents that is based predominantly on determination of maximum tolerated dose (MTD), a more suitable paradigm involving surrogate markers and functional endpoints is crucial. We, therefore, hypothesize that integration of intermediate biologic endpoints, which reflect interaction with or functional impact on the target, will provide key information for determining optimal biologic dose (OBD), as well as the foundation for further study of biomarker identification of responsive patients in subsequent Phase II studies. With such an undertaking, there must be effective cooperation between clinical and laboratory investigators, in addition to experts in the field of molecular imaging, in order to evaluate the ability of targeted drugs to modulate, interact with, or inhibit specific molecular and biochemical targets. Such cooperation is found at the M.D. Anderson Cancer Center (MDACC), where great emphasis is placed on clinical and translational drug development, as evidenced by our tremendous infrastructure! and educational support for clinical trials research. Indeed, MDACC has extensive facilties and extremely experienced faculty and personnel for data management, quality control, regulatory oversight, specimen acquisition, patient care, and translational studies to identify pharmacodynamic and molecular biomarkers. The significance of our proposed research is that it should advance the development of new cancer therapeutics by providing the groundwork for elucidating how response correlates with target impact, hence laying the foundation for successful personalized cancer treatment. [unreadable] [unreadable] [unreadable]